As the result of the increasing use of abdominal imaging in standard medical practice, pancreatic cysts are being identified with increasing frequency. Management of these cysts is concomitantly becoming a major clinical problem (1, 2). These lesions occur in more than 20% of patients examined at autopsy (3), in as many as 19.6% of patients evaluated by MRI (4-6), and as many as 2.6% of patients evaluated by CT (7, 8). In the vast majority of cases, the cysts are identified as incidental findings in patients undergoing imaging for symptoms unrelated to pancreatic pathology. But once a cyst is identified, it poses a challenging, life-long management problem (1, 2, 9-13). Some cyst types, are virtually always benign, some are low-grade malignant, and others are precursors to invasive pancreatic ductal adenocarcinomas (PDAs), and PDAs are associated with a dismal prognosis (14-17). The distinction among cyst types is therefore critical for the effective management of patients with pancreatic cysts. Unfortunately, it is often difficult to determine the type of cyst from conventional clinical, radiographic, or cytologic findings (1, 2, 9-16, 17)
Approximately 40% of cysts are non-neoplastic “pseudocysts” that develop as a complication of alcoholic, biliary, or traumatic acute pancreatitis (14-16, 17). They are managed medically or by surgical drainage without resection. The neoplastic cysts (60% of the total cysts) are predominantly of four types: intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and serous cystadenomas (SCAs), and solid pseudopapillary neoplasms (SPNs) (18). SCAs, IPMNs, and MCNs are benign (i.e., non-invasive), but IPMNs and MCNs have the potential to progress to PDAs (i.e., become invasive lesions) if not surgically excised (17). Based on the age of patients undergoing surgical resection, some reports have suggested that there is a 5-year lag time from diagnosis of a large non-invasive IPMN (average age 63.2 years) to diagnosis of an invasive cancer stemming from the IPMN (average age 68.1 years). This provides a broad time window for curative resection if premalignant cysts are accurately identified (19). SPNs are regarded as low grade malignant, but they can be cured by surgery if they are detected and removed prior to their widespread metastasis (20).
IPMNs are the most common type of neoplastic cyst, accounting for ˜25% to 35% of the total cysts, while SCAs, MCNs, and SPNs account for ˜20%˜10%, and ˜5% of pancreatic cysts, respectively. SCAs (FIG. 1A) are lined by cuboidal glycogen-rich epithelium with centrally placed round nuclei without atypia (17). SCAs (FIG. 1B) arise within the normal ductal system and are lined by columnar mucin-producing cells which often form large papillary projections into ductal lumina (17). The epithelium of SCAs is associated with a rich capillary network (21). MCN's (FIG. 1C) are also lined by columnar mucin-producing cells, but in contrast to IPMNs, the neoplastic epithelium is associated with a characteristic ovarian-type stroma, and the cysts do not communicate with the ductal system (17). MCNs nearly always occur in the body or tail of the pancreas in women, while IPMNs and SCAs can occur in any part of the pancreas and in both sexes. SPNs (FIG. 1E, F) are technically solid tumors but the vast majority of them undergo cystic degeneration that clinically and radiographically mimic the other types of pancreatic cystic neoplasms (20). Like MCNs, they generally occur in women and do not communicate with the ductal system. Histologically, SPNs consist of uniform poorly cohesive cells supported by delicate small blood vessels. The neoplastic cells of SPNs do not have a normal counterpart in the normal pancreas.
To date, a definitive diagnosis of neoplastic cyst type can usually only be obtained following histopathologic examination of surgically obtained specimens. The decision to surgically resect pancreatic cysts is based on the presumed type of cyst along with clinical parameters. Resection is performed on all cysts which are presumed to be SPNs. In contrast, cysts diagnosed as SCAs only require resection if they are large or cause symptoms. Finally, patients with presumptive MCN or IPMNs undergo surgery if they meet certain criteria such as rapid growth, or the presence of a mural nodule. (1, 2, 9-13). The pre-operative diagnosis of surgically-excised cysts has been shown to be erroneous in one third of cases, which can lead to unnecessary surgical procedures (22). For example, there is no need to excise small asymptomatic SCAs, as they have essentially no malignant potential (17). However, SCAs can be suspected to be IPMNs and therefore be surgically excised (1, 2, 22). Major surgical procedures are often required for removal of these cystic lesions, so more accurate pre-surgical diagnosis has the potential to reduce the cost, morbidity, and occasional mortality associated with unnecessary surgery.
Cyst fluids can easily and safely be obtained from patients with pancreatic cysts by endoscopic aspiration (23-28). These fluids are often acellular and therefore not typically useful for cytologic diagnosis. However, such fluids can be analyzed for the presence of biochemical abnormalities, including those of DNA, and have the potential to inform diagnosis and improve the management of patients with these lesions (23-28). To set the stage for future molecular genetics-based diagnostic assays, we have here determined the sequences of the exomes, including all annotated coding genes, of representative cases of all four types of neoplastic cysts.
There is a continuing need in the art to distinguish among cyst types without the need to obtain surgical samples for the effective management of patients with pancreatic cysts.